tbuckley/cabot-search huggingface dataset:
Using EHR data to compare survival disparities in major cancer types.
Authors: Wanting Cui, Joseph Finkelstein
Journal: Journal of Clinical Oncology (2022)

e18517 Background: The aim of our study is to provide a comparative overview of survival disparities in 5 major cancer types: breast cancer, colorectal cancer, lung cancer, multiple myeloma and prostate cancer, within one health system in New York City. Using this approach, we aim at initial assessment of potential drivers of disparities in cancer survival, especially for those who deceased in a short amount of time after diagnosis. Methods: A limited dataset was generated from electronic medical records from Mount Sinai Health System for the five cancer types from January 2003 to November 2020. We extracted 2 subsets from the original dataset: patients who survived less than 1 year between diagnoses and death, and patients who have survived for over 5 years after diagnoses. We performed logistic regression to investigate the effect of demographical factors on patients’ duration of survival after cancer diagnosis. Results: There are 1280 patients who survived less than 1 year and 20,816 patients who survived over 5 years. Although there are less overall colorectal cancer and lung cancer diagnoses, there are significantly more patients who deceased within a short of period of time from these 2 cancers, comparing to the other 3 cancer types. Race was an important factor. There was significantly more proportions of black patients deceased in a short period of time than in a long time after diagnosis. Percentage of individuals with short survival in Blacks and Whites was respectively 41.4% and 22.2% for lung cancer, 9.8% and 7.1% for colorectal cancer, 2.9% and 0.7% for breast cancer, 6.8% and 4.0% for multiple myeloma, and 1.4% and 0.8% for prostate cancer. This disparity was observed in all five cancer types. When comparing within race, there were significantly higher proportions of black patients survived a short time than those survived a long time for all 5 cancer types. When comparing with other races, black patients who were diagnosed with lung cancer or breast cancer were more likely to be deceased in a short time after diagnosis compare to white patients. And Hispanic patients with lung cancer were also at risk of shorter survival length compared to white patients. Thus, promoting routine cancer screening is important in black and Hispanic communities. Conclusions: Logistic regression identified factors increasing likelihood of shorter survival that included older age, and being male, Black or Hispanic. We concluded that further analysis of broader spectrum of risk factors is warranted.
TiNivo-2: A phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor.
Authors: Toni K. Choueiri, Laurence Albiges, Rana R. McKay, Sumanta K. Pal, Hans J. Hammers, Daniel Yick Chin Heng, Katy Beckermann, Vijay Kasturi, Robert J. Motzer
Journal: Journal of Clinical Oncology (2022)

TPS4605 Background: Tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (aRCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile (Rini et al Lancet Oncol 2020). Tivozanib was approved by the FDA on March 10, 2021, for the treatment of patients with aRCC who had progressed on 2 or more prior systemic therapies. Tivozanib was combined with Nivolumab in the phase 1b/2 TiNivo trial (NCT03136627), showing an objective response rate of 56%, disease control rate of 96%, median PFS of 18.9 months and a tolerable safety profile (Albiges et al Ann Oncol. 2021). Methods: TiNivo-2 (NCT04987203) is a phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following 1-2 lines of therapy including an immune checkpoint inhibitor. Eligibility criteria include age &gt;18 years, clear cell RCC, ECOG PS 0-1, and disease progression during or following at least 6 weeks of treatment with ICI for RCC. Subjects will be stratified by IMDC risk category and whether ICI was received in most recent line of treatment or not. Subjects will receive tivozanib 1.34 mg orally once daily for 21 consecutive days followed by 7 days off, on the monotherapy arm, and tivozanib 0.89 mg at the same schedule in addition to nivolumab 480mg intravenously every 4 weeks on the combination arm. Study assessments include CT scan or MRI of the chest, abdomen, and pelvis every 8 weeks following Cycle 1 Day 1 for 2 years and every 12 weeks thereafter until disease progression is confirmed by independent radiology review (IRR). The primary objective is to compare the progression-free survival (PFS) of tivozanib in combination with nivolumab to tivozanib. A sample size of 326 subjects, with 191 events will provide at least 80% power to detect a 50% improvement in PFS, 12 mos v. 8 mos, as assessed by an IRR. Secondary endpoints include assessment of overall survival (OS), objective response rate (ORR), and duration of response (DoR), as well as safety and tolerability. Exploratory endpoints are to assess the quality of life (FKSI-DRS and EORTC QLQ C-30) and to investigate the pharmacokinetics of tivozanib. TiNivo-2 is actively enrolling and planning to open at 190 sites in the United States, and the European Union. Clinical trial information: NCT04987203.
Survival analysis of the randomized phase II trial to investigate androgen signaling inhibitors with or without androgen deprivation therapy (ADT) for castration-sensitive prostate cancer: LACOG 0415.
Authors: Fernando Cotait Maluf, Andrey Soares, Diogo Assed Bastos, Fabio A. B. Schutz, Eduardo Cronemberger, Murilo Luz, Suelen P. S. Martins, David Queiroz Borges Muniz, Flavio Mavignier Carcano, Oren Smaletz, Fábio A Peixoto, Andrea J Gomes, Felipe Melo Cruz, Fabio Franke, Daniel Herchenhorn, Rosemarie Gidekel, Taiane Francieli Rebelatto, Rafaela Gomes, Vinicius Carrera Souza, Andre P. Fay
Journal: Journal of Clinical Oncology (2022)

5076 Background: LACOG 0415 is a phase II, open-label, clinical trial evaluating ADT-free alternatives for advanced castration sensitive prostate cancer (CSPC). Methods: Patients with locally advanced, high-risk biochemical recurrence or metastatic CSPC were randomized (1:1:1) to receive ADT with abiraterone acetate plus prednisone (ADT+AAP), apalutamide alone (APA), or apalutamide with AAP (APA+AAP). The primary endpoint of the trial was the proportion of patients who achieved PSA≤0.2 ng/mL level at week 25. Patients without disease-progression and with clinical benefit after week 25 were allowed to maintain treatment at the discretion of physicians. Herein, we presented the outcomes of 2 year-overall survival (2y-OS) and time-to-treatment failure (TTF). The time-to-event endpoint was estimated by Kaplan-Meier method and compared by stratified log-rank test. Results: 128 patients were randomized to the ADT+AAP (n = 42), APA (n = 42), and APA+AAP (n = 44) arms. At week 25, PSA≤0.2 ng/mL was observed in 75.6% (95%CI 59.7%-87.6%), 60.0% (95%CI 43.3%-75.1%), and 79.5% (95%CI 63.5%-90.7%) of patients in the ADT+AAP, APA, and APA+AAP arms, respectively. 110 patients continued treatment after week 25. At the 2-year visit, 80 (62.5%) patients remained on the study medication. Median TTF was 24.0 months (95%CI 23.3 - 24.0) with ADT+AAP, 24.0 months (95%CI not estimated) with APA, and 24.0 months (95%CI 13.0-24.0) with APA+AAP. The main reasons for treatment discontinuation were disease progression (n = 8, 6.3%), toxicity (n = 10, 7.8%), death (n = 6, 4.7%), withdrawal (n = 4, 3.1%), and other (n = 19, 14.8%). The estimated proportion of patients who were alive at 2 years (2y-OS rate) was 92.5% (95%CI 84.3-100) with ADT+AAP, 87.9% (95%CI 77.9-97.8) with APA, and 92.7% (95%CI 84.8-100) with APA+AAP (p = 0.5926). 2y-OS was 92.9% (95% CI 85.3 - 96.2) in patients with PSA ≤ 0.2 ng/mL at week 25, while 2y-OS was 85.0% (95% CI 72.9-97.1) in patients with PSA &gt; 0.2 ng/mL at week 25 (p = 0.1250). Conclusions: Patients with advanced CSPC treated with ADT+AAP, APA, or APA+AAP had high rates of PSA response and favorable 2y-OS. PSA ≤ 0.2 ng/mL at week 25 seems to be a surrogate prognostic predictor of OS in advanced CSPC. In the overall sample, patients with PSA ≤ 0.2 ng/mL at week 25 had higher 2y-OS rate than those with PSA &gt; 0.2 ng/mL at week 25 (92.9% vs. 85.0%), however without statistical significance. Clinical trial information: NCT02867020.
The landscape of <i>NRG1</i> fusions based on NGS in Chinese solid tumor patients.
Authors: Shaohua Yuan, Hui Chen, Liwei Wang, Xiaowei Dong, Aodi Wang, Kai Wang
Journal: Journal of Clinical Oncology (2022)

e15073 Background: Neuregulin 1 gene ( NRG1) fusions are oncogenic in various tumor types and represent an emerging potential therapeutic target. In the previous reports, NRG1 fusions are overall rare (0.12%) in the Western population, being seen most frequently in NSCLCs. The incidence of NRG1 fusions in a variety of solid tumors based on NGS has been explored limitedly in Chinese patients. Methods: FFPE samples and matched peripheral blood were collected for NGS based 450 cancer genes panel assay and RNA panel assay.Somatic variants were analyzed following CAP/CLIA-certificated workflows, including Single Nucleotide Variant (SNV), Copy Number Variation (CNV), large insertion and deletions (Lindel) and gene rearrangements. Results: A total of 47 patients harboring NRG1 fusions and four of them were detected in RNA level. Non-small cell lung cancer (NSCLC) was the most common cancer type with the incidence of 0.19% (25/13089). The followed cancer types were bone sarcoma, breast carcinoma, pancreatic adenocarcinoma and colorectal carcinoma with the frequency of 0.30% (3/973), 0.16% (3/1850), 0.14% (3/2098) and 0.07% (3/4344) respectively. CD74 (10.1%), SLC34A2 (10.1%) and WRN (4.3%) represented the most common NRG1 fusion partners, other known partners contained CDH1, HMBOX1, ADAM5 and UNC5D. In total, 76.6% of the partners were novel partners, and the most common break points of NRG1 were intron5 and intron1. The 47 NRG1 fusion patients evenly distributed in female (49%) and male (51%), and 44.7% were at advanced stage (stage ≥ III). The median age was 57 years old (range, 8-86 years old) and the median TMB was 3.3 muts/Mb (range, 0-30.5). TP53 (48.9%), CDKN2A (14.9%) and ERBB2/FGFR1/MUC16/SMAD4 (12.8%) were the most common co-occurred mutated gene. In the alterations of ERBB2, 50% were amplifications and 2 patients were breast carcinoma. Only one patient showed ALK fusion and one showed FGFR1 fusion. Among all patients, 8.5% included p.G12X mutation of KRAS and 10.6% included alterations of EGFR with two L858R and two 19del mutations. Conclusions: This study revealed NRG1 fusions in approximately 0.19% of Chinese NSCLC tumor pts and presented the frequency of same common tumors. Also the genomic and clinical feature were analysed. NGS panel sequencing and OrigiFus algorithm showed the advantage of detecting NRG1 fusion and providing structure information of partners which could potentially guide more precise treatment options.
SOURCE beyond first-line: A survival prediction model for patients with metastatic esophagogastric adenocarcinoma after failure of first-line palliative systemic therapy.
Authors: Steven C. Kuijper, Marieke Pape, Nadia Haj Mohammad, Thymen Van Voorthuizen, Aeilko H. Zwinderman, Rob Verhoeven, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2022)

4037 Background: Prediction models for survival may aid shared decision making between physicians and patients. Prior models have been developed that predict survival for patients with potentially curable esophagogastric cancer and patients with metastatic esophageal cancer who start first-line therapy (the SOURCE models). The aim of this study was to develop and internally validate a registry-based clinical prediction model, called SOURCE beyond first-line, for survival of patients with metastatic esophagogastric cancer after failure of first-line palliative systemic therapy. Methods: Patients with unresectable or metastatic (synchronous or metachronous) esophageal or gastric cancer who received first-line systemic therapy (N = 1067) between 2015-2017 were selected from the Netherlands Cancer Registry. Follow-up data were retrieved in 2019. Patient, tumor and treatment characteristics at primary diagnosis and at progression of disease, were used to develop the prediction model. A Cox proportional hazards regression prediction model was developed through forward and backward selection using Akaike’s Information Criterion. The model was internally validated through 10-fold cross-validations to assess performance on unseen data. Model discrimination (C-index) and calibration (slope and intercept) were used to evaluate performance of the complete and cross-validated models. Results: The final model consisted of 10 patient, tumor and treatment characteristics. The C-index was 0.75 (0.74-0.77), the calibration slope 0.99 (0.98-0.99) and the calibration intercept 0.02 (0.01-0.02). Internal cross-validation of the model showed that the model performed adequately on unseen data: C-index 0.79 (0.76-0.80), calibration slope 1.02 (1.00-1.04) and calibration intercept -0.01 (-0.01-0.02). Conclusions: The SOURCE beyond first-line model predicted survival with fair discriminatory ability and good calibration, and is a valuable addition to the existing SOURCE prediction models. In the future this model will be integrated in an online decision support tool that can be used in clinical practice to aid personalized treatment.
Development of a predictive model for emergency room utilization and unanticipated hospital admission in patients receiving cancer treatment for solid tumor malignancies.
Authors: Catherine Watson, Brooke Alhanti, Congwen Zhao, Laura J Havrilesky, Brittany Anne Davidson
Journal: Journal of Clinical Oncology (2022)

e18674 Background: Unanticipated healthcare resource utilization, in the form of either emergency department utilization (EDUs) or hospital admission (HA), is an indicator of lower quality of cancer care. The objective of this study was to develop a comprehensive predictive model for emergency department utilization and hospital admission (HA) for patients with solid tumors who received chemotherapy within 30 days. Methods: We abstracted electronic health data on oncology encounters from all patients receiving systemic therapy chemotherapy for solid tumors from March 01, 2015 to August 21, 2020. Patients included in the cohort met the following criteria:1) Ages &gt; = 18 years old 2) Diagnosed with any solid tumor (3) Had any oncology treatment plan related to their solid tumor diagnosis; 4) Received at least one chemotherapy during March 01, 2015 through August 21, 2020. We defined a primary composite outcome of emergency visit or unanticipated hospitalization within 30 days after the encounter. Patient information was abstracted. We developed a predictive model for the primary outcome using LASSO logistic regression modeling. To evaluate the model, we calculated the Area Under the Receiver Operator Characteristic (AUROC) and the calibration slope. Results: 12,917 unique patients with 134,641 encounters were included. Of these, 9100 (6.7%) of encounters were ED visits or hospitalizations. 714 patients (5.5%) had at least one ED visit or hospitalization within 30 days of treatment; patients at highest risk for this outcome included those with pancreatic cancer, lung cancer and ovarian/endometrial cancer (9.1%, 7.4% and 6.8% respectively). 38 variables were identified as contributing to the LASSO model. The top predictors, in order of importance, were fever, hypernatremia, hypotension and low albumin. The model’s AUC was 0.83, indicating good model sensitivity to outcome. Conclusions: Approximately 7% of healthcare encounters in patients undergoing treatment for solid malignancies were ED visits or hospitalizations. Identifying patients at highest risk for this outcome may prevent unnecessary resource utilization and optimize patient care during cancer treatment. The model developed in this study demonstrated good sensitivity and could be implemented in clinical practice to allow for preventive outpatient interventions. Work is ongoing to integrate this model into clinical care at our institution.[Table: see text]
Identifying targetable markers of resistance to dual TORC1/2 inhibition in endometrial cancer cell lines.
Authors: Katie McGreal, Sarah Crafton, Jason David, Colin W. Stets, Nicholas Grosenbacher, James Lin Chen, John L. Hays
Journal: Journal of Clinical Oncology (2022)

e17633 Background: For patients with endometrial cancer, the PI3K/AKT/mTOR pathway is an attractive target due to dysregulation of the pathway secondary to commonly found genetic alterations. Previous trials of mTOR inhibitors in endometrial cancer have shown modest clinical activity and tolerability. Here we present a proteomics based approach to identify novel partners that will enhance the efficacy of dual TORC1/2 inhibition. Methods: Five endometrial cell lines (AN3CA, ECC, HEC1A, HEC1B, RL952) were treated with the TORC1/2 inhibitor TAK228 or vehicle for one hour and protein concentrations were analyzed by reverse phase protein arrays (RPPA). We examined baseline protein and changes in individual proteins after treatment with TAK228 to determine correlations with sensitivity to TAK228. Identified proteins were then targeted with single agent pharmacologic inhibition and cytotoxicity measured by XTT analysis. Target inhibition was validated using WB analysis. Cooperativity in cytotoxicity for relevant combinations was measured using the methods of Chou-Talalay. Other phenotypic endpoints including migration, cell cycle alterations by flow cytometry and cell growth using live cell imaging were also collected. Results: Based on proteomics analysis, altered phosphorylation of CHK1(S296), CHK2(T68) and increasing concentration of VEGFR2 were strongly correlated with TAK228 resistance. TAK228 (TORC1/2, IC50 4-20nM), AZD7762 (CHK1/2, IC50 15-160nM), LY2603618 (CHK1, IC50 260nM-7.5mM) and cediranib (VEGFR2, 800nM-1mM) all had significant cytotoxic effects as individual agents on multiple endometrial cell lines. AZD7762 in combination with TAK228 led to synergism in all cell lines tested (mean combination index, 0.2-0.8). Single agent AZD7762 increased the number of cells in S-Phase and decreased cellular migration. Addition of recombinant VEGF-A to cell culture enhanced resistance to TAK228 in a dose dependent manner as measured by cell growth assays using live cell imaging. Combination of cediranib and TAK228 also showed significant synergism in multiple cell lines. Conclusions: RPPA identified changes in phosphorylated CHK1/2 and total VEGFR2 as being correlated to resistance to dual TORC1/2 inhibition with TAK228 in multiple endometrial cancer cell lines. While single agent activity of TORC1/2, CHK1/2 and VEGFR2 inhibitors showed varying activity, combinations of TAK228 with either cediranib or AZD7762 showed significant synergism in multiple cell lines. Clinical examination of these combinations agents may prove useful in recurrent endometrial cancer.
The effect of tumor purity on next generation sequencing of colorectal cancer.
Authors: Tao Yu, Xinyu Zhao, Xianchao Guo, Qi Zhang, Shiyao Zhang, Zhicheng Zhao, Tong Liu, Gang Liu
Journal: Journal of Clinical Oncology (2022)

e15557 Background: Considerable advancements have been made in tumorigenesis, therapeutic target and diagnostic markers of colorectal cancer by next generation sequencing (NGS). However, almost tumor tissues contain the non-cancerous components, such as inflammatory cells and stromal cells. The DNA from these cells may cause the fraction of reads containing somatic mutations from tumor cell decreases. Therefore, it’s necessary to systematically clarify the relationship between tumor purity and NGS in colorectal cancer. Methods: Formalin fixed and paraffin embedded (FFPE) blocks were collected and cut into 20-40 8 um-thick sections used for genomic DNA extraction. Sections were evenly divided into two groups, purity group and non-purity group. In purity group, the sections were stained with Histogene (Life Technologies), a PCR-compatible tissue stain. And the tumor samples were accurately collected on the section under the microscope. No special treatment before sequencing in non-purity group. Next-generation sequencing (NGS) based on a 425-gene panel was performed in tumor samples and matched plasma samples. Results: 30 samples were included in this study. 687 non-synonymous mutations were found in purity group, 271 mutations were found in non-purity group, including 247 common mutations in both group, 440 purity-specific mutations (false negative mutations), and 24 non-purity-specific mutations (false positive mutations). The Variant allele fraction (VAF) of common mutations in purity group was significantly higher than that in non-purity group (Wilcoxon test: P&lt; 0.05). The number of mutations in purity group was higher than that in non-purity group, but no significant difference between them (10.5[3, 154] vs 9[3-90], Wilcoxon test: P&gt; 0.05). The false positive ratio (the number of false negative mutations/the number of common mutations) was negatively correlated with tumor purity (Spearman rank correlation test: r = 0.4280, P = 0.02596). When the tumor purity below 30%, 86% false negative mutations belong to high-frequency mutation (VAF &gt; 10%) in purity group. Only 8% false negative mutations belong to high-frequency mutation when purity above 30%. The false positive ratio (the number of false positive mutations/the number of common mutations) wasn’t correlated with tumor purity (Spearman rank correlation test: r = 0.1387, P= 0.4648). Conclusions: Tumor purity is an importance role in precise NGS of colorectal cancer. Higher tumor purity can ensure the integrity of NGS.